Roles of acetate metabolism in the virulence of Candida albicans

醋酸盐代谢在白色念珠菌毒力中的作用

• 批准号: 8137392
• 负责人: Michael C Lorenz
• 金额: $ 5.85万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2011-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137392
• 关键词: Acetates; Acetyl Coenzyme A; Affect; Animals; Antibiotics; Antifungal Agents; Aspergillus; Bacteria; Bacterial Infections; Biochemical; Biological Models; Biology; Candida albicans; Carbon; Cells; Consumption; Data; Development; Diagnostic; Disseminated candidiasis; Dominant-Negative Mutation; Dyes; Environment; Enzymes; Ethanolamines; Fatty Acids; Fluorescence Microscopy; Fucose; Genes; Genomics; Glucose; Goals; Homeostasis; Human; Human body; Immune system; In Vitro; Infection; Intervention; Intracellular Transport; Knock-out; Laboratories; Link; Measures; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molds; Molecular Genetics; Morphogenesis; Morphology; Mutation; Mycoses; Nutrient; Nutritional; Organism; Pathogenesis; Phagocytosis; Phagolysosome; Phenotype; Process; Production; Propylene Glycols; Protein Family; Proteins; Publishing; Regulation; Research Personnel; Role; Saccharomyces cerevisiae; Site; Source; Starvation; Stress; Toxin; Virulence; Work; Yeasts; ato protein; cell type; drug development; extracellular; fitness; fungus; in vivo; killings; macrophage; meetings; microbial; microorganism; mortality; mouse model; novel; pathogen; programs; research study; response; stress tolerance; success; sugar; transcription factor

DESCRIPTION (provided by applicant): The yeast Candida albicans is the most important fungal pathogen of humans and can infect virtually any body site, highlighting a remarkable adaptability that allows it to thrive in widely disparate conditions. Mortality is higher than in comparable bacterial infections, partly due to serious deficiencies in diagnostic and treatment options. The projects outlined here derive from a comprehensive genomic analysis of the response of C. albicans to phagocytosis by macrophages, a key antifungal cell type, in which a massive metabolic reorganization accompanies a well-studied morphogenetic program. We have focused on the metabolic changes, which are centered on the key intermediate acetyl-CoA and have shown that mutations in several genes important in the production, consumption or transport of this compound reduce virulence in a mouse model of disseminated candidiasis. Together these studies have shown that C. albicans finds and uses non-preferred carbon sources during infection. Consistent with its unique ecological niche as a mammalian commensal, the regulatory networks that govern the metabolic pathways necessary to assimilate such compounds are significantly different than those in the related, but non-pathogenic, yeast Saccharomyces cerevisiae. Further, we have evidence that these metabolic changes also directly affect processes conventionally thought to be more central to virulence, such as filamentation and pH regulation. In particular, we find that C. albicans can actively change extracellular pH to a dramatic degree (up to 3 units) and hypothesize that that this occurs within the mammalian phagolysosome as a protective measure. We propose here studies to understand acetyl-CoA homeostasis as it relates to virulence, pH modulation, and morphogenesis and outline experiments to decipher how C. albicans has adapted the regulation of alternative carbon utilization to meet its in vivo needs. Lay Summary: Fungal infections kill -10,000 people (and rising) per year in the U.S., making further studies directed towards eventual drug development imperative. This proposal uses an isolated immune system- fungal model system using Candida albicans, the most important fungal pathogen, to study basic cellular metabolism, changes in which are suggested to be a key component of the infection process.

描述（由申请人提供）：酵母白色念珠菌是人类最重要的真菌病原体，几乎可以感染任何身体部位，突出显示出显着的适应性，使其可以在广泛不同的条件下繁衍生息。死亡率高于可比的细菌感染，部分原因是诊断和治疗方案的严重缺陷。这里概述的项目来自对白色念珠菌对巨噬细胞吞噬作用的反应的全面基因组分析，巨噬细胞是一种关键的抗真菌细胞类型，其中大规模代谢重组伴随着一个良好的形态发生程序。我们专注于代谢变化，这些变化集中在关键的中间乙酰-COA上，并表明，在这种化合物的生产，消耗或运输中重要的几种基因中的突变减少了在传播念珠菌的小鼠模型中的毒力。这些研究共同表明，白色念珠菌在感染过程中发现并使用了非偏见的碳源。与其作为哺乳动物共生的独特生态基础相一致，它控制着同化此类化合物所需的代谢途径的调节网络与相关的，非致病性的酵母菌糖含量相关的化合物明显不同。此外，我们有证据表明，这些代谢变化也直接影响通常认为是毒力的过程，例如细丝和pH调节。特别是，我们发现白色念珠菌可以主动将细胞外pH变为戏剧性的程度（最多3个单位），并假设这发生在哺乳动物的吞噬体内部作为保护措施。我们在这里提出的研究旨在了解乙酰-COA稳态，因为它与毒力，pH调节，形态发生和轮廓实验有关，以解读白色念珠菌如何适应替代碳利用的调节以满足其体内需求。摘要摘要：在美国，真菌感染每年杀死-10,000人（和增加），这是针对最终药物开发的进一步研究。该提案使用使用白色念珠菌（最重要的真菌病原体）使用孤立的免疫系统真菌模型系统来研究基本的细胞代谢，这些变化被认为是感染过程的关键组成部分。